About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

June 30, 2010

As mentioned here before, there have been several episodes where people have thought to have discovered a new metal-catalyzed coupling reaction that uses some metal not known for such things. But closer examination often reveals that ridiculous trace amounts of palladium, copper, or other more reactive metals are still in the system and responsible for all the results.

The most recent candidate is been a series of gold-catalyzed reactions. Gold complexes have been quite fashionable in recent years, after a long period where they were considered next to useless. But perhaps things have gone a bit too far. A new paper in Organic Letters examines some gold-catalyzed couplings and finds, well. . .

Experimental reports claim that Au(I) is selective and very active, for instance, toward cross coupling of aryl halides with acetylenes (“Pd-free Sonogashira” for example), in the presence of mild bases. Surprisingly, this intriguing process has not been investigated mechanistically. We decided to set out experiments that would explain mechanistically the Pd-free cross-coupling catalysis with gold, but in fact what we are reporting is our failure to find a plausible mechanism. Furthermore, our experiments suggest that the presence of adventitious Pd might explain the positive “Pd-free Sonogashira” catalysis reported. . .

It's the oxidative addition step (the first one in the cycle) that makes things go off the rails. Gold complexes (at least the ones reported) just don't seem to be able to do it. On the other hand, as the authors mention, even high-quality gold often has a bit of palladium in it, and that bit is all it takes.

Culturing bacteria is usually a pretty quiet affair. Bacteria aren't too noisy, and the equipment used to keep them happy isn't too dangerous. But there are exceptions. If you're going to culture anaerobes, you need somewhat more advanced technique, what with all that oxygen-is-deadly business. A professional-grade culture chamber for those beasts is usually filled with a mixture of about 80% nitrogen, 10% carbon dioxide, and 10% hydrogen. And those you'll be getting from three compressed gas cylinders, which is how they were doing it in a lab at the University of Missouri until Monday afternoon. . .

Well, regular readers will be expecting this to be a story of someone who did not remember to Treat Compressed Gases With Respect, but that's not the case. No, this is what happens when you don't Treat Hydrogen With Respect - and everyone in the audience who's had a hydrogenation reaction get frisky on them will be nodding their head in agreement at that thought. Somehow, enough hydrogen and enough oxygen got together around an anaerobic culture hood, and the mixture found an ignition source, and well. . .
Problem is, just about any hydrogen/air mixture will do. Anything from about 4% hydrogen in air to about 75% will ignite, and everything except the two ends of that range will go ahead and explode if given the chance. (Only acetylene is worse in that regard). And it doesn't take much to set it off, either, which is the other nasty thing about working with hydrogen. A static-electricity spark is plenty, as are the sparks generated by electrical switch contacts and the like.
As you can see, the lab was not improved by the resulting explosion. The latest report I have is that four people were injured, one seriously enough to still be in the hospital, although their condition has been upgraded to "good".

Initial reports were that this was due to human error, although everyone seems to be backing off that judgment until an official investigation is finished. At any rate, the local fire department stated Monday night that the problem was one or more people in the lab "not being familiar with the warning systems designed to alert them when the hydrogen level was approaching explosive limits (and) the gas was left on". If that was the case, then. . .you ignore a hydrogen level alarm at your peril. And here are seventeen blown-out windows, four people who are lucky not to have been killed, and one demolished lab as evidence.

Update: I had a link up to a commercial anaerobic culture chamber for illustration, but (as the manufacturer points out) these use cylinders of premixed gas with only 5% hydrogen which obviates this very problem. I thought it best to take down the link so that no confusion results - after all, it wasn't the model that was being used in this incident (and in fact would have avoided it completely). I should add that the email I received about this out was exactly the sort of courteous and informative request I have no problem responding to, as opposed to some others that have come in over the years.

(Photos are courtesy of the Missourian and the Columbia Fire Department).

June 29, 2010

Now, this could get quite interesting. A recent paper in PNAS talks about "downsizing" biologically active proteins to much shorter mimics of the alpha-helical parts of their structures. These show a good deal more stability than the parents, and show a sometimes startling amount of biological activity.

The building block for all this is the smallest helical peptide yet reported, a cyclic pentapeptide (KAAAD) curled as as a lactam between residues 1 and 5. Joining two or more of these up give you more turns, and replacing the alanines gives you plenty of possible mimics of endogenous proteins. An analog of nociceptin turned out to be the most potent agonist at ORL-1 ever described (40 picomolar), and an analog of RSV fusion protein is, in its turn, the most potent inhibitor of that viral fusion process ever found as well.

Meanwhile, the paper states that these constrained peptides were stable in human serum for over 24 hours, as very much opposed to their uncyclized counterparts, which are degraded rapidly. (Exocyclic amino acids, when present, do get degraded off in a time span of hours, though).

I'm quite amazed by all this, and I'm still processing it myself. I'll let the authors have the last word for now:

"This work is a blueprint for design and utility of constrained α-helices that can substitute for α-helical protein sequences as short as five amino acids. . .The promising conformational and chemical stability suggests many diverse applications in biology as molecular probes, drugs, diagnostics, and possibly even vaccines. The constrained peptides herein offer similar binding affinity and/or function as the proteins from which they were derived, with the same amino acid sequences that confer specificity, while retaining stability and solubility akin to small molecule therapeutics. . ."

Phil Baran of Scripps has a paper out on the "ideal synthesis" of complex molecules. It's mostly a review of a number of his group's own syntheses, but it's done in light of his definition of "ideal": all bond-forming steps, with no protecting group manipulations or oxidation-state maneuvering.

That's a tough standard, but many biosynthetic routes reach 100% against it. I think that the highest figure from one of the Baran group's own syntheses is 84%, but he emphasizes that comparing these figures across the synthesis of different molecules isn't too meaningful, since they each carry their own issues. Comparing different routes to the same molecule is what he has in mind; it's a pity that no one else is ever going to make maitotoxin.

He also emphasizes that "ideality" isn't the only consideration in a synthesis. It gets at some key issues, but others (availability of reagents, ease of experimental procedures or purifications) can trump ideality out in the real world. You certainly see that in process chemistry in the drug industry. A reliable procedure that always gives the same (but lower) purity will win out over a temperamental one that sometimes gives wonderful material but sometimes craps out. And an elegant-looking route that gives a small amount of an intractable impurity isn't so elegant, compared to a slightly longer one that delivers material that's easily cleaned up.

The same goes for reagents. Ideally, you'd want to be able to buy all of them, and cheaply, too. But that's where the comparison with those 100% ideal biosynthetic routes breaks down. The enzymes that accomplish them are nothing if not bespoke reagents, doing one thing only but nearly perfectly. And there's that matter of a billion years of evolutionary overhead to factor in to the development costs. Of course, the other great thing about enzymes is that they're catalytic, and can just keep turning over reactions constantly. If they were one-time-use, like many of our reagents from the catalogs, it wouldn't matter how incredibly high-yielding and specific they were; the horrendous waste of time and material required to produce them for just one transformation would rule them out. Average those expenses out over the turnover numbers of a typical enzyme, though, and things look very good indeed.

I think that Baran's criteria are well worth keeping in mind, although I also think that most synthetic chemists already think this way, to one degree or another. I always gritted my teeth when I put on a protecting group during my total synthesis days, because I knew that I was adding another step (and more potential trouble) down the line when it had to come off again. Mind you, I was putting the thing on to avoid what I saw as even more immediate trouble, but I guess that's one of the things that Baran is saying, that it's time to try to stop making such deals if we can.

June 28, 2010

Earlier this year we had a paper from the Nicolaou lab on the synthesis of the ABCDEFG ring system of maitotoxin. Now I see that a synthesis of the QRSTU domain has arrived. That's what, twelve rings down? Only twenty more to go, guys. This piece is ". . . appropriately functionalized . . . for further elaboration and coupling with suitably activated neighboring ring systems of maitotoxin for the purposes of constructing larger domains of the natural product." My deepest sympathies to all concerned.

Last summer I mentioned a shareholder lawsuit against Schering-Plough over the way that the ENHANCE clinical data were handled for Vytorin. One of the interesting features here is that the plaintiffs are claiming that the company knew that the clinical trial was showing troublesome data, but elected to sit on the numbers for as long as possible - and they're introducing a series of posts on Cafe Pharma as evidence. These seem to foretell the 2008 announcement of the bad numbers in early 2007, with disturbing accuracy.

Now, as Jim Edwards points out, this case has not gone away. In fact, the most recent attempt to get it thrown out has failed, and former CEO Fred Hassan faces a possible deposition on the matter. This will be quite interesting to watch, since Merck is on the hook for any judgments that might result. Stay tuned. . .

June 25, 2010

Yesterday morning I went on and on about the low quality of much of what gets published in the scientific literature. And indeed, the low end is very likely of no use to anyone, except (apparently) the people publishing it. But what to do with the rungs above that?

For organic chemistry, those are occupied by papers that report new compounds of little interest to anyone. But you never know - they might be worth someone else's time eventually. It's unlikely that any of these things will be the hinge on which a mighty question turns, but knowing that they've been made (and how), and knowing what their spectra and properties are could save someone time down the line when they're doing something more useful. These are real bricks in the huge construction of scientific knowledge, and while they're not worth much, it's more than zero. That's the value I assign to the hunks of mud that some people offer instead, or the things that look like real bricks but turn out to be made out of brick, yes, but about one millimeter thick and completely hollow.

So what to do with work that's mostly reference data for the future? It shouldn't have to appear in physical print, you'd think. How about the peer-reviewed journal part? Well, peer review is not magic. As it stands, that sort of information is the least-reviewed part of most papers. If someone tells you that they've made Compound X and Compound Y, and the synthesis isn't obviously crazy, you tend to take their word for it. It's a rare reviewer that gets all the way down to the NMR spectra in the supplementary material, that's for sure. And if one does, and the NMR spectra look reasonably believable, well, what else can you do? Even so, every working chemist has dealt with literature whose procedures Just Don't Work, and all those papers passed some sort of editorial review process at some point.

No, peer review is not going to do much to improve the quality of archival data. If someone really wants to fill up the low-level bins with junk, there's not much stopping them. You could sit down and draw out a bunch of stuff no one's ever made before, come up with plausible paper syntheses of all of it, use software to predict reasonable NMR spectra (which you might want to jitter around a bit to cover your tracks), and just flat-out fake the mass spec and elemental analyses. Presto, another paper that no one will ever read, until eventually someone has a reason to make similar compounds and curses your name in the distant future. The problem is, such papers will do you no real good, since they'll appear in the crappiest journals and pick up no citations from anyone.

Perhaps there should be a way to dump chemical data directly into some archives, the way X-ray data goes into the Protein Data Bank. That wouldn't count for much, but it would capture things for future use. Having it not count much would decrease the incentive for anyone to fill it full of fakery, too, since there would be even less point than usual. And before anyone objects to having a big pile of non-peer-reviewed chemical data like this, keep in mind that we already have one: it's called the patent literature, and it can be quite worthwhile. Although not always.

June 24, 2010

From the Wall Street Journal, here's the history of the Novartis compound fingolimod, from its intellectual origins as a cicada fungus extract to today, when it might become the first oral medication for multiple sclerosis.

If fingolimod makes it, it'll also be the first drug I'm aware of that has a flippin' n-octyl chain hanging off it - a flagrant violation of everything that a medicinal chemist learns in their first month on the job. Hydrophobic bulk, metabolism bait, entropic penalty - well, there it is. I'm not suggesting that we all go out and slap pennzoilane and crisco-cene side chains on our lead drug candidates, but it's worth remembering that the race is not always to the swift, nor the battle to the strong.

That's what this article at the Chronicle of Higher Education could be called. Instead it's headlined "We Must Stop the Avalanche of Low-Quality Research". Which still gets the point across. Here you have it:

While brilliant and progressive research continues apace here and there, the amount of redundant, inconsequential, and outright poor research has swelled in recent decades, filling countless pages in journals and monographs. Consider this tally from Science two decades ago: Only 45 percent of the articles published in the 4,500 top scientific journals were cited within the first five years after publication. In recent years, the figure seems to have dropped further. In a 2009 article in Online Information Review, Péter Jacsó found that 40.6 percent of the articles published in the top science and social-science journals (the figures do not include the humanities) were cited in the period 2002 to 2006.

As a result, instead of contributing to knowledge in various disciplines, the increasing number of low-cited publications only adds to the bulk of words and numbers to be reviewed. Even if read, many articles that are not cited by anyone would seem to contain little useful information. . .

If anything, this underestimates things. Right next to the never-cited papers are the grievously undercited ones, most of whose referrals come courtesy of later papers published by the same damn lab. One rung further out of the pit are a few mutual admiration societies, where a few people cite each other, but no one else cares very much. And then, finally, you reach a level that has some apparent scientific oxygen in it.

The authors of this article are mostly concerned about the effect this has on academia, since all these papers have to be reviewed by somebody. Meanwhile, libraries find themselves straining to subscribe to all the journals, and working scientists find the literature harder and harder to effectively cover. So why do all these papers get written? One hardly has to ask:

The surest guarantee of integrity, peer review, falls under a debilitating crush of findings, for peer review can handle only so much material without breaking down. More isn't better. At some point, quality gives way to quantity.

Academic publication has passed that point in most, if not all, disciplines—in some fields by a long shot. For example, Physica A publishes some 3,000 pages each year. Why? Senior physics professors have well-financed labs with five to 10 Ph.D.-student researchers. Since the latter increasingly need more publications to compete for academic jobs, the number of published pages keeps climbing. . .

We can also lay off some blame onto the scientific publishers, who have responded to market conditions by starting new journals as quickly as they can manage to launch them. And while there have been good quality journals launched in the past few years, there have been a bunch of losers, too - and never forget, the advent of a good journal will soak up more of the worthwhile papers, lifting up the ever-expanding pool of mediocre stuff (and worse) by capillary action. You have to fill those pages somehow!

If this problem is driven largely by academia, that's where the solution will have to come from, too. The authors suggest several fixes: (1) limit job applications and tenure reviews to the top five or six papers that a person has to offer. (2) Prorate publication records by the quality of the journals that the papers appeared in. (3) Adopt length restrictions in printed journals, with the rest of the information to be had digitally.

I don't think that those are bad ideas at all - but the problem is, they're already more or less in effect. People should already know which journals are the better ones, and look askance at a publication record full of barking, arf-ing papers from the dog pound. Already, the best papers on a person's list count the most. And as for the size of printed journals, well. . .there are some journals that I read all the time whose printed versions I haven't seen in years.

No, these ideas are worthy, but they don't get to the real problem. It's not like all the crappy papers are coming from younger faculty who are bucking for tenure, you know. Plenty more are emitted by well-entrenched groups who just generate things that no one ever really wants to read. I think we've made it too possible for people to have whole scientific careers of complete mediocrity. I mean, what do you do, as a chemist, when you see another paper where someone found a reagent to dehydrate a primary amide to a nitrile? Did you read it? Of course not. Will you ever come back to it and use it? Not too likely, considering that there are eight hundred and sixty reagents that will already do that for you. We get complaints all the time about me-too drugs, but the me-too reaction problem is a real beast.

Now, I realize that by using the word "mediocrity" I'm in danger of confusing the issue. The abilities of scientists are distributed across a wide range - I doubt if it's a true normal distribution, but there are certainly people who are better and worse at this job. But I'm complaining on the absolute scale, rather than the relative scale. I know that there's always going to be a middle mass of scientific papers, from a middle mass of scientists: I just wish that the whole literature was of higher quality overall. A chunk of what now goes into the mid-tier journals should really be filling up the bottom-tier ones, and most of the stuff that goes into those shouldn't be getting done in the first place.

I suppose what bothers me is the number of people who aren't working up to their potential (although I don't always have the best position to argue that from myself!) Too many academic groups seem to me to work on problems that are beneath them. I know that limits in money and facilities keep some people from working on interesting things, but that's rare, compared to the number who'd just plain rather do something more predictable. And write predictable papers about it. Which no one reads.

June 23, 2010

Aficionados will remember that Warner-Lambert nearly killed Lipitor along the way because they felt that the statin market was too crowded. Well, now Lipitor's patent is going to finally expire next year, which will make it even harder for anyone to turn a buck on anything higher-priced.

So Eli Lilly is, yes, bringing a statin of their own to market. Livalo (pitavastastin) will try to make headway based on a slightly lower price than Crestor (the big dog, after next year, among the patent-protected statins) and a different metabolic profile that might decrease drug-drug interactions.

Lilly brought this one in from Kowa of Japan, and it's hard to see how they'll get too many people excited about it. And while I certainly understand to need to make some money, one way or another, making it this way doesn't add mmuch to the case for Big Pharma innovation, does it? Maybe there are enough people out there who will benefit from another alternative - but no one can say that the world was waiting for another statin, that's for sure.

Exelixis has long been a bit of a puzzle to outside observers. The company has developed a number of clinical candidates in oncology (many of them kinase inhibitors, I believe). In fact, for a while there, they seemed to have developed more clinical candidates than a company that size should have been able to manage. It was a bit alarming to employees of larger companies in the area.

And figuring out what the structures of these things were wasn't so easy, either. I once had the unenviable assignment of trying to break down a stack of their patent applications to see if I could find the lead structure for one of their compounds, and after a week or so I had to concede. None of my usual tricks worked - untangling and charting out the synthetic pathways from the experimental section to see the common threads, looking for sudden upticks in the amounts of intermediates or final compounds being prepared, looking to see if some compounds had been more completely characterized than others, and so on. No, these folks had done a fine job of sweeping up after themselves, and over the years I've run into other people who came to the same conclusion.

The company has had a long relationship with Bristol-Myers Squibb. There have been many twists and turns, but in 2008 the companies agreed to develop a compound called XL-139. (You won't quite be able to figure it out from that Exelixis page, but that announcement also marked the end of one of the broader agreements that the two companies had signed). Later that year came an announcement (also on that link above) about two more kinase inhibitors, XL-184 and XL-281, whose status hadn't been resolved earlier.

Now comes word that XL-184 has been returned to Exelixis. The press release, as press releases will, makes it seem as if the problem was that the compound was just too darn good:

"Given the recent progress of BMS' wholly-owned oncology pipeline and positive data generated by XL184, Exelixis and BMS were not able to align on the scope, breadth and pace of the ongoing clinical development of XL184."

They say that they're pleased to have the chance to develop the compound outside the meddling influence of BMS (well, not quite in those words naturally). But I'll bet they're not pleased to have to do it without BMS cash. Having the drug sent back makes you think that the larger company put it in the category of "Nothing we can't live without", although it's true that XL-184 is surely worth more to Exelixis. (Development of the other compound, XL-281, is apparently continuing).

My guess is that kinase inhibitors of this sort just look a lot less attractive than they did a few years ago. Several of them have made it to market, and while they can be profitable, the field is getting crowded. Mind you, they're all different from each other, but sorting out what works in the clinic is a long process. None of them seem (so far) to do anything dramatic against the most common tumor types. (Here's a recent article on just that problem). What Exelixis will make of XL-184 remains a mystery, probably to them just as much as to anyone else.

June 22, 2010

Andrew Witty of GSK is warning European governments (Greece and Spain especially) against whacking drug prices in an effort to save money. And while he's got a point, I think that the people who have been let go by the company in recent months won't appreciate the headline "Cut now and regret later, warns pharma chief". Or maybe they will, depending on their tolerance for straight-up black humor.

The folks at Cresset sent me a note about a free download of some software that they've developed for molecular fields (an approach you can read more about here). Fieldview is a free tool for trying this out yourself, and can be had here. Worth a look for the computationally curious, especially at the price. . .

Someone completely outside the industry asked me the other day what I thought about the FDA. I replied that I had a lot of sympathy for them, actually. There's almost no way that they can avoid being yelled at by one group or another. You know - they're a bunch of foot-dragging nitpickers who are keeping effective medicines (things used in other industrialized countries, yet!) off the market here. Oh, hold it, it's Tuesday already - they're actually a bunch of incompetent industry shills who let all kinds of useless, toxic stuff through because they can't be bothered to do their jobs.

That's the sort of thing. If you want a good example of this, take a look at Mylotarg. Wyeth developed this oncology agent years ago for some forms of leukemia. It's a monoclonal antibody to CD33 (a cell-surface receptor found on leukocytes), conjugated to ozogamicin, a fairly aggressive chemotherapy agent. It was approved back in 2000 under "accelerated approval" rules, which are supposed to bring drugs for life-threatening conditions to market more quickly. The requirement is that companies continue to study such drugs after they're marketed, though.

Well, the studies have been completed on Mylotarg. It's not a very widely used drug, since it's only indicated for people 60 and older with particular forms of leukemia who aren't candidates for the more common therapies. But the numbers are in. . .and it turns out that people die more quickly while taking it than while taking the standard of care. Oh, dear. The drug has now been pulled from the market.

And there you have the FDA's dilemma: if they had sat on Mylotarg longer and required more studies, this probably wouldn't have happened. On the other hand, Wyeth might have decided to abandon it at that point - and not everything that gets accelerated approval is a Mylotarg. Some compounds that could actually help people could get lost that way. It's a real tightrope, and the rope is set up completely differently for every new drug. There's no way to get all these decisions right, but for life-threatening diseases, letting through more iffy compounds is still probably the right way to do it, I think.

Update: fixed all sorts of formatting and spelling issues, after taking a break from my real job to have a look (!)

I haven't commented on the controversy over Boehringer Ingleheim's drug for female libido, flibanserin. An FDA advisory panel voted it down on Friday, and it wasn't close: 10-1 against whether the drug showed efficacy, and unanimously against its side effect profile. I really don't see how the drug is going to make it back from that kind of reception.

The press coverage of this compound has not been good. Far too many headlines have called it "Female Viagra", which is ridiculously off-base. Viagra, for its part, does absolutely nothing for the libido; it's plumbing, a pure cardiovascular effect. The assumption (a reasonable one, for many men) is that the desire is already there. Meanwhile, flibanserin is a central nervous system agent, affecting the mental state of sexual satisfaction, not any cardiovascular sequelae. The drugs are completely different.

And the FDA panel's problem (one of their problems) with the drug was that it doesn't seem to do much for desire, either. We can argue all day about whether low desire is a disease or not, but even if someone does want to do something about it, flibanserin doesn't seem to be the answer.

Boehringer is taking a lot of criticism for bringing the drug this far, actually. It was originally developed as an antidepressant, but during the trials reports came in of the sexual effects in female patients, so they repurposed it - taking the drug out of a crowded field and into completely new territory. You can admire that as showing flexibility, or you can worry that the company found a possible drug and then went shopping for a disease, with a willingness to invent one if it didn't quite exist.

I don't know where I stand on that latter point; I've no idea what the statistics are on low sexual desire as a problem (and I'm willing to bet that what numbers might exist have whopping error bars on them). But I think that we're not going to be revisiting this topic any time soon. The FDA panel officially encouraged Boehringer to continue research, but the vote tallies are not the sort of thing that would encourage anyone.

June 18, 2010

Linda Wang at C&E News tells me that she's looking for recent graduates in the New England area for a story she's working on about the current job-search conditions.

She'd be interested in hearing from recent grads who have managed to find positions, those who are currently looking, as well as those who are technically working but underemployed. Her e-mail (de-spamified) is l-underscore-wang-at-acs-dot-org, or you can call her at 202-872-4579.

Here's something that oddly ties together the last couple of days of posting around here: the failure of the Human Genome Project to jump-start drug discovery as the "most significant economic event of the past decade". (Thanks to Jonathan Gitlin for the tip).

I have to say, I hadn't thought of it in those terms. My first thought is that this is a negative event, something that didn't happen, so it's pointless to speculate about what might have been. But the author, Mike Mandel, is also talking about the opportunity cost of all the genomics frenzy, which is a real consideration. That time and money could have been spent somewhere else, doing something more useful. Where would we be then?

I've wondered about that myself, having seen first-hand what happened. Many companies really did cut a deep notch in their development pipelines during that era, abandoning (to one degree or another) their traditional approaches while piling resources into the genomics gold rush. (The current economic environment is cutting a similar gouge into the list of start-up companies - many of the ones that "normally" should have formed during the last couple of years just haven't happened).

Mandel's larger point, though, is something I'm not so sure about. He's talking about all the manufacturing jobs that haven't been created by the basic research, holding that these are the ones with real economic effect. But even if the genomics era had been wildly successful, we wouldn't have seen manufacturing jobs picking up from it for some years - 2008, maybe? His charts, which tend to cover from the early 1990s to date, are reflecting other issues entirely.

Then the talk turns to balance of trade:

Now let’s turn to trade. China, India, and the rest of the developing countries sell the U.S. an increasingly diverse array of goods and services. What does the U.S. provide in return? There’s the usual list of suspects, such as commercial aircraft (which is increasingly drawing on parts made outside of the country). But they are not enough to avoid a huge trade deficit, even now.

The logical candidate for the next wave of U.S. exports should have been biotech products and knowledge. The U.S. is the acknowledged world leader; the research is expensive and lengthy; the production processes are complicated, delicate, require skilled technicians, and cannot be easily offshored. And the category–treatments to deal with major medical problems–is something that everyone wants.

But what happened? Without compelling new biotech products, the big pharma companies were “me-tooed” to death. In fact, pharma trade went from roughly balanced to a big deficit.

That's illustrated by another chart from 1994 on. But what it's showing isn't what he thinks it's showing. It illustrates the move to less costly manufacturing sites, which would have taken place whether genomics would have delivered or not. The only mitigating factor is that any big protein-based biologics would have had a better chance of being produced domestically, but production of all the small-molecule drugs that might have come out of the genomics frenzy would have migrated offshore just like everything else.

And what if the genomics revolution had delivered? We'd have a lot more drugs on the market, none of which would be selling cheaply, you can be sure - and there would be even more anxiety over the amount of our GDP going to health care. (Never mind that some of these drugs would, one hopes, be keeping people from going into even more expensive therapies later - people don't seem to pay attention to that, either). So overall, I take the point about opportunity cost. But his broader economic implications, as least as regards the US economy alone, don't seem to me to hold up.

A reader points me to this discussion, which is trying to figure out what the most useful discovery made via bioinfomatics is so far. There's a $100 prize for the winning suggestion, just to keep the discussion moving (and no, I don't anticipate offering cash bounties around here any time soon!) The early going seems to have ended up in the "Hold it, that's not bioinformatics, is it?" ditch, but that's not a useless discussion, either.

So if you have some suggestions, hop over there and add them to the fray, or vote for the ones that you like so far. I'm racking my brain a bit myself.

June 17, 2010

Jim Edwards has a good post up about financial efficiency among the big drug companies. If you plot out their revenue versus expenses (S,G&A), you see that all the big outfits are basically the same (here's an enlarged version of the graph). Abbott's a bit toward the top end of the narrow range, and AstraZeneca's toward the bottom, but there's not much to choose from. This despite several of the companies on the chart having done whalloping huge mergers during the period shown, mergers which were supposed to improve efficiency. As Edwards shows, though, the best that can be said so far is that (in some cases) things have moved from a bit below average all the way up to. . .average.

It's interesting to compare that ratio to those found at other companies and in other industries. The rule of thumb is that a dollar of SG&A is worth three in revenue. The big drug companies look to have ratios of about 3.2 to 3.5 or so. For apples versus oranges comparisons, Pier 1 is at 3, Best Buy is at 4.2, and Dollar General is at 4.4. Tiffany is 2.4, and CVS is an impressive 7.1.

Another thing to check is the trend over a longer time period. This Nature Reviews article suggests (in its table 1) that the overall ratio for all publicly traded drug companies has been deteriorating slowly since 1975, going from above 3 down to 2.6 or 2.7. (And there are indeed some companies who bring down the average - Genzyme, for example, is at 1.9, partly because of its recent troubles, and Shire is around 2 as well).

Another interesting thing is how Amgen is included on the graph. Perhaps it's an artifact, but what it looks like is that the company starts out like a high flier, and gradually sinks into the same mire as the rest of the big pharma companies. Parallels between that and Amgen's real situation are, I hope, coincidental.

June 16, 2010

I'm told, by a source I have no reason to doubt, that today and tomorrow Merck (and former Schering-Plough) process chemists are having individual meetings to find out whether they're being kept on or not. The Pharmaceutical Sciences department is supposed to go through the same process next week, and Med Chem looks to be on the agenda soon. More details as I hear about them.

One of the folks over at Chemistry Blog has run into a shortage: he and his labmates have tried to order (-) sparteine from every supplier in the book, and there's none to be had. So if anyone has a big dusty bottle of it sitting around, you might drop these desperate chemists a line. But that got me thinking about the way things suddenly dry up like this.

The situation is different than for an industrial chemical shortage, like the acetonitrile crunch that we went through a while back (and which has long since eased up). It's quite unusual for a bulk chemical like that to go down; several factors hit all at once in that case, and it affected an awful lot of people who needed the solvent. But fine chemicals are much weirder. When you trace some of them back to their real sources, you sometimes find that there are really only a couple of people in the world at any given time making some of these things. Or, in many cases, you find that there's no one making it at all - someone made a bunch a few years ago for some reason, sold the excess to a supplier, and everyone else has been buying it from that same bottle ever since.

So when one of these small-scale itemsevaporates, the reason can be supply: no one makes it any more. Or it can be demand-driven: a single drug company's scale-up group can deplete the world's commercial supply of some strange little molecule when they suddenly switch to a 500-gram run. Everyone working in such a group knows to call all the suppliers when they have a prep calling for some weirdo starting material, and they'll often take the precaution of ordering whatever's out there to be had. (That serves as a cushion while they contract someone else to crank out a batch or figure out how to make it themselves). Naturally, you'd rather have your drug candidates depend only on things that can be ordered in tank car lots, but that's just not always possible.

So it could be that someone needed a lot of (-) sparteine for an asymmetric synthesis recently, and bought up the existing world stocks. But this one sounds like more of a supply problem. There would appear to be customers out there, who have been draining the existing stocks, but no one's been able to replenish them. TCI apparently stated that it's the starting material for (-) sparteine that has become unavailable, but that sounds a bit funny, since it would surprise me if the material on the market is synthetic. Sparteine is a naturally occurring alkaloid, found in several species of plant, and it's very hard to compete with isolation of the natural product in those cases.

Perhaps TCI means that the usual plant source is unavailable - that's happened before, too. A spike in Tamiflu demand a few years ago suddenly sent the price of star anise up to record levels, since the chiral starting material (shikimic acid) in the usual synthesis was most conveniently isolated from that source. But for sparteine, it looks as if the isolation comes from plants in the broom family, which are not exactly rare shrubs, so I'm not sure what's going on. Any ideas?

June 15, 2010

Now here's an idea to think about: improving patient compliance for their prescriptions by paying them to stay on track. The article goes into some of the benefits and potential risks - for example, some people will deliberately act like noncompliers in order to get on the pay system.

But in general, lack of compliance in taking prescribed drugs is a pretty big problem. And fixing it takes more than exhortations or appeals to one's better nature:

“We’ve made our best efforts to say, ‘If you didn’t take your beta blocker or asthma medicine, you have a greater chance of ending up with a heart attack or dead or hospitalized,’ ” said Dr. Lonny Reisman, Aetna’s chief medical officer. “It’s going to take more. It’s going to take incentives.”

I'm just glad that the insurance companies are taking the lead on this one. I can imagine the press a drug company would get for suggesting it.

That's the University of California system versus Nature Publishing Group, in case you were wondering. As the Chronicle of Higher Education reports, there's a mighty dispute brewing about the cost of electronic access:

On Tuesday, a letter went out to all of the university's faculty members from the California Digital Library, which negotiates the system's deals with publishers, and the University Committee on Library and Scholarly Communication. The letter said that Nature proposed to raise the cost of California's license for its journals by 400 percent next year. If the publisher won't negotiate, the letter said, the system may have to take "more drastic actions" with the help of the faculty. Those actions could include suspending subscriptions to all of the Nature Group journals the California system buys access to—67 in all, including Nature.

The pressure does not stop there. The letter said that faculty would also organize "a systemwide boycott" of Nature's journals if the publisher does not relent. The voluntary boycott would "strongly encourage" researchers not to contribute papers to those journals or review manuscripts for them. It would urge them to resign from Nature's editorial boards and to encourage similar "sympathy actions" among colleagues outside the University of California system.

NPG's testy response is here, and this is the reply from California. The current points of dispute are how much the publishers are actually raising the prices (site license fees versus the base rate) and how much of a discount the UC system is getting already.

Could there really be a UC boycott? They're large enough (and productive enough) to make that a reasonably credible threat. The Nature journals will certainly survive without submissions from the UC system, although over the last six years they've contributed over five thousand papers to them. But the real danger, I think, is the damage that this could do to Nature's position, and to the whole idea of the high-prestige journals. The scientific publishing world has been feeling the earthquake tremors for some time now. The traditional model (1. Start an academic journal. 2. Charge whopping subscription fees. 3. Profit) seems to be breaking down, in the same way that many other traditional content-distribution pricing models have been.

Nature and its related journals, along with the other top-tier publications, have managed to stay on top (and to charge accordingly). But journal prestige is an artificial construct, a fiction by common consent. A journal has a good reputation because it's hard to publish in and can afford to reject all but the most high-impact papers that it's offered. If people stop offering such papers to it, its prestige will decline. The big-splash papers will go somewhere else, and will perhaps manage to signal their importance in some other way than by the name of the journal they appear in.

This dispute will be worth watching closely. Which side will give in? Will a UC boycott be effective, and could it spread? Remember, from one perspective, other journals have an interest in seeing this happen, since they'll now see the papers that NPG won't. But they might also fear the same thing happening to them if this succeeds. . .

June 14, 2010

Well, this could be nothing, or it could be big trouble: there's a report out that taking the angiotensin antagonists (the various "sartans") might be linked to increase risk of cancer. A meta-analysis of several large trials, reported in Lancet Oncology, patients in the treatment groups showed a 7.2% incidence of new cancer diagnoses, versus 6% for the control groups. These are large sample sizes, so that difference has a p-value of 0.016.

The authors wisely refuse to take the data any further, and call for more investigation, which certainly seems warranted. The whole renin-angiotensin system is certainly involved in angiogenesis, and thus could very plausibly have effects in oncology. But the surprising thing is that there's evidence that blockade of the receptors could actually cut down on tumor formation, too. If you'd taken a survey last week, you'd probably have gotten a lot of people to bet that these drugs would actually have a protective effect.

So what's going on? It's going to be quite a while before we find out. But an awful lot of people take these drugs, and now they're all wondering what to do. . .

The New York Times reminded its readers the other day about something that people in medical research have known for quite some time: the human genome has not exactly turned out to be an open book full of readily usable data about human diseases.

It does make a person cringe to go back and read the press releases and speeches that were made back when the genome was first announced. How about Bill Clinton's statement that the genome sequence would "revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases"? Or Francis Collins, predicting "a complete transformation in therapeutic medicine"? He's got about five more years on that one, but I'm not holding my breath.

As I've written here before, though, there was already a deep sense of nervousness among the people searching the sequences for disease clues - not to mention the nervousness among the people who had given them huge piles of money to do so. When the total estimated number of genes came out far lower than most people expected, there was a collective "Hmmm. . ." across the field. That number meant that the simpler possibilities for gene sequence-protein-disease linkage could already be ruled out - complicated things were clearly going on in transcription, translation, and further downstream.

That certainly doesn't mean that genomic sequencing has been a waste of time. It's been a tremendous boon, actually, because this complexity was out there waiting to be uncovered and understood. It's no one's fault that it hasn't led to speedy drug discovery; biology isn't set up for our convenience. And the further improvements that we've seen in sequencing speed and accuracy are going to be crucial if we're to have any chance of figuring out what's going on.

Comes now a highly placed pharma executive warning about America's competitive edge in the life sciences:

The American pharmaceutical and life sciences industry is in danger of losing its edge in innovation, said John Lechleiter, chairman and CEO of Eli Lilly & Co. today at the Detroit Economic Club.

Lechleiter blamed the loss on tax and immigration policies over the last 10 years that have reduced research and investment funding and driven away foreign-born, U.S.-trained scientists.

Now, as regular readers know, I'm not an opponent of outsourcing. But you can't have it both ways, sending as much research and development as you can to India, China, and what have you, and then complaining about the US losing its R&D position. Can you?

It's no secret that Alzheimer's disease has been a disastrous area in which to do drug discovery. Every large drug company has had failures in the area, and many smaller ones have gone out of business trying their hands. (I had several years in the field myself earlier in my career, trying three different approaches, none of which panned out in the end).

Now the Coalition Against Major Diseases has announced an open-access database of clinical trial results from failed drug candidates in the area. J&J, GlaxoSmithKline, Abbott, SanofiAventis, and AstraZeneca have contributed data from 11 failed drug candidates, and more look to be on the way from other companies. I hope that Eli Lilly, Merck (their own compounds and those from Schering-Plough), and Pfizer all join in on this - right off the top of my head, I can think of failed drugs from all of them, and I know that there are plenty more out there. (Pfizer seems to have dodged a question about whether or not they're participating, to judge from that Wall Street Journal article linked to above).

It'll be difficult to comb through all this to extract something useful, of course. But without sharing the data on these compounds, it would be utterly impossible for anything to come out of their failures. I think this is an excellent idea, and well worth extended to other therapeutic areas.

June 10, 2010

I've received a letter from John Kingma, the Chief Financial Officer of Nativis. I reproduce it below word-for-word (Here's the PDF of the original, in case anyone would like to check):

Dear Dr. Lowe,

The scientific nature of your blog seems to have taken a turn for the worse with the negative personal attacks on John and Lisa Butters and othe rmatters related to Nativis. The comments have gone far beyond reasoned scientific debate, skepticism and criticism. In fact, the overall tone seems to have degenerated into something resembling the Internet bulletin boards of old, with personal attacks, sexual comments and statements that may well amount to libel and defamation of character.

It appears to us that that the same person, using multiple names, is responsible for many of the negative personal comments (indications are that this is a person who bears a personal grudge against John Butters, and who now seems intent on ruining his reputation and that of Nativis). It seems clear to us that you have permitted unprofessional, bizarre, and even potentially activity prohibited by law to be conducted by this commenter and others on your blog site, activity that clearly overrides the scientific debate.

No one in the Nativis family has experienced anything so outrageous and unprofessional as the content of your blog site. I don't know if the current non-scientific banter is what you intended for your blog - essentially now a forum for personal attacks. Not only have you allowed theses attacks to be posted, you have also been selective in posting (screening out) information that would be more favorable to Nativis, such as the positive pre-clinical research data that John Butters provided you, showing how drug signal therapy reduced tumors in mouse models.

Moreover, apart from personal attack comments, your blog also contains comments from a person who announced his attempts to gain access to Nativis's facility. In fact, he visited Nativis's site, posing as a representative of your blog, The Pathfinder. When he was turned away by security, he reportedly took photographs or videos through office windows. His actions were reported and encouraged on your site. His actions may well have been illegal.

We have asked counsel to take a look at what is happening on your blog and the activities by commenters promoted there, and to recommend a course of action. But everyone at Nativis would rather get past this unfortunate situation and spend 100 percent of our time advancing our technology.

In that regard, may we suggest that in the best interest of all parties that you moderate your blog, focus on the scientific debate, delete all personal attacks and prevent personal attacks from occurring in the future? That would seem fair and reasonable, while also keeping the scientific debate going.

Thank you, in advance, for the consideration. I look forward to your response.

Sincerely,

John E. Kingma
Chief Financial Officer

Well. I suppose that the rest of this post should begin with "Dear Mr. Kingma:"

I am, as you see, in receipt of your letter of June 9. Allow me to comment on it, so that we may understand each other.

Your first objection is that the tone of some of the comments to my two posts on Nativis have "gone far beyond reasoned scientific debate". A less charitable observer might say that the claims that Nativis makes for its technology have long since occupied that territory. But I've actually tried to be charitable. Until your letter arrived, most of the criticism I'd received from readers and colleagues in the industry was that I'd been far too tolerant in my discussion of your company.

Your CEO, in addition to sending me papers on such disparate subjects as the Mossbauer effect (and offering generously to send along a large book on quantum electrodynamics), did indeed provide a graph of what is said to be the effect of your most advanced. . .well, let's call it a "therapeutic agent" in a mouse model. This does not help me as much as you seem to believe it does. Imagine some other company claiming that they can show effects in a mouse xenograft model though the intervention of invisible pink unicorns - and providing a dose-response curve as proof. Extraordinary claims, which yours surely are, require extraordinary evidence, and I don't see how you can possibly provide enough in a blog forum to convince your critics. Besides, this would be a waste of your time. You will surely be generating a tremendous amount of data in preparation for your company's IND application, and I certainly can't ask you to share all of it. Convince the FDA, and you'll have gone a long way to convincing everyone else.

Now, to your observations about my blog's comment section: I do not actively moderate it, except to occasionally remove duplicate posts. No real moderation has been needed: the tone of discussion around here is unusually civil, for the most part. It's especially so compared to the rest of the blog world and the Internet as a whole - not just "of old", but every day of the week. If no one in the "Nativis family" has ever experienced anything so outrageous as the contents of this blog, permit me to observe that you appear to have led sheltered lives.

Believe me, you will hear worse from other people as you go on developing your company's approach to drug therapy. I mean this in the best possible way, but the material that Nativis uses to explain and promote its technology does not inspire confidence in trained observers. I assume that you're well aware of this; if you're not, you should be. And that's fine - huge breakthroughs in the sciences often have that effect on people. But the problem is, nonsense has the same effect. If I may quote the late Carl Sagan on this very problem, "They laughed at Galileo. They laughed at Einstein. But they also laughed at Bozo the Clown."

Your company's claims are so startling, and so far beyond what most scientists would assume to be possible, that you truly have no alternative but to fall into one of those two categories. A red nose, a fuzzy wig, and floppy shoes are waiting for anyone who makes such claims. Your job is avoid being fitted for them. To that end, you do not have to convince me, or any random bunch of people on the internet. You have to convince the patent offices, the journal editors, and the regulatory authorities. My advice is to devote your time and effort to that task, and to stop worrying about what people say about you on blogs.

Worse things have been said on this site about other (far larger) companies; worse things are said all over the internet a thousand times a second. I certainly do not endorse the making of defamatory comments about people, but I fear that some of the very comments you might object to might not be seen that way by every observer. If I start taking down every comment that offends anyone who writes to me, there will be no end to it.

If you read my posts, you will see that I have not encouraged anyone to engage in illegal conduct. That goes for the entire 8-year archives of the blog, for that matter. I did not encourage anyone to visit your site in any way, and did not comment when someone reported that they did so. I live and work on the other side of the country from you, and my readers are responsible for their own actions. By the way, if the person you speak of did identify themselves as a representative of "The Pathfinder", as you state, then their connection to a blog called "In the Pipeline" is unclear.

As to whether some individual is engaging in a campaign of defamation against your company and your CEO, I can see no evidence of that in my blog's records. The uncomplimentary comments seem, from what I can tell, to have come in from a wide variety of separate sources - you truly have brought people together. On the other hand, some of the glowing endorsements and defenses of your company have come in under different names from the exact same IP addresses. Make of that what you will.

Mr. Kingma, you (and John Butters, and all the other officers and employees at Nativis) should be out there working to revolutionize the entire drug industry. If you can do what you say you can, that's exactly what will happen. Any scientist on the trail of something this wonderful, this huge - and potentially this profitable - would not allow anything to deter them from claiming their place in history. Go do that. I'll be overjoyed if you manage to pull it off. But having heard, after only two blog posts, from both the CEO and the CFO of your company makes me wonder about how you choose to use your time.

June 9, 2010

Yancey Ward, who comments over at Megan McArdle's site at The Atlantic, has started a discussion over there on drug patent issues. There are a couple of things worth talking about here (such as how to handle combination therapies), but I wanted to bring up a particular issue first to see what the readership here makes of it:

". . .It is getting increasingly difficult to patent small molecules because their structures are increasingly found in the ever growing patent literature for completely different targets. I know for a fact that a lot of projects begin on a less than optimal structure for reasons of patentability alone."

How much of a problem is this? I know that sometimes it can be a real roadblock, particularly in areas where particular structural motifs get (over)used. I've been in on some of those projects myself. And "useful chemical space with no prior art" is a large (but finite) resource, which we are using up, as people have realized for years.

But it would be very interesting - although probably impossible - to know how many total projects across the industry have to start from a bad position because of patentability issues. That can be partly a problem of your own screening collection, which is something every company has to guard against. If you have some big, long-running projects that have cranked out a lot of similar-looking chemical matter in certain areas, these things are naturally going to be over-represented in your corporate screening files. If they're really useful structures, the challenge (after a while) becomes how to avoid starting off yet another program from the same general structures, in order to avoid their complex IP and shrinking freedom to operate. The less-trampled your compound collection is, the better off you'll be when something hits from it.

That said, the only projects I've been on that came to a halt because of patentability trouble did so because someone else popped up in the middle of things with coverage of exactly what we were working on. It happens! Other projects have gotten rather complex, as the trends in the active compounds kept pushing us closer to someone else's exemplified chemical matter, but we generally can find a way around that. Now, if we tried to total up the amount of time and money spent in that way, in working around other people's claims, that might truly add up to something alarming. . .

For a long time now, people have been searching for a way to raise HDL levels (the so-called "good cholesterol"). Statins will lower your LDL, while raising HDL just a pinch, but no one has a good, robust way to do it. (Niacin is probably the closest thing, but not everyone can take it). Many have tried, and failed, with Pfizer's CETP inhibitor torcetrapib being the most notably horrendous.

Now there's a completely new way to regulate HDL, and it comes from a direction you might not expect: the brain. A new paper in Nature Neuroscience demonstrates that melanocortin signaling, ghrelin and GLP-1 change HDL levels, through both altered cholesterol synthesis and uptake. Since these are involved in a number of ways in food intake and metabolism, it makes sense (in retrospect) that there would be a lipoprotein connection, but this does seem to be a dramatically direct one. (More and more, it appears that many metabolic processes that were thought to be more peripheral are under some sort of central control, actually). As the authors put it:

An integrated neuroendocrine control of food intake, body weight and glucose homeostasis, as well as cholesterol metabolism and cardiovascular lipid exposure, would connect all of the hallmarks of the metabolic syndrome. Therapies promoting the increase of HDL levels have been proposed for the prevention of atherosclerosis in humans. . . We speculate that modulation of neuroendocrine circuits may offer therapeutic opportunities to prevent cardiovascular disease.

Yes, indeed. It's not going to be easy, though. Ghrelin and GLP-1 have already been looked at for diabetes and obesity therapy, and they're tricky to deal with. Small-molecule ghrelin antagonists are known - as I should know - and there have been many reports of melanocortin receptor ligands as well. Of course, the question will be how many other things you might mess with at the same time, but it's going to be very interesting and worthwhile to unravel these.

June 8, 2010

Here's a good piece from Megan McArdle on the pipeline problem in the drug industry. It'll be familiar ground to many readers of this blog (and not just because I was a source for the piece), but it's good to get the word out on these things to as wide an audience as possible.

A reporter from a major newspaper has contacted me while working on a story about GlaxoSmithKline's new R&D structure. They've noticed a lot of comments to posts here, and wonder if anyone would like to provide their opinions as to how things are going. If anyone's interested, drop me an e-mail, and I'll provide contact information. At that point, I'll drop out of the process entirely.

This time last year, Medarex made all sorts of headlines with their antibody ipilimumab. A press release from the Mayo Clinic made it sound like a miracle cure for prostate cancer; the company's stock soared, and they were acquired not long afterwards by Bristol-Myers Squibb. I wrote about ipilimumab once, and I still get email from people asking me if I know how they can possibly get some for their relatives with cancer.

As Jim Edwards points out at Bnet, though, this week's ASCO meeting has results for the drug that are more in keeping with what we've come to expect. The antibody had real effects in metastatic melanoma patients, and that's a good thing, because that's a particularly hard situation to show anything useful. (And all too many melanoma patients present after the disease has already gone metastatic, for that matter). From the data that BMS presented, there appears to be no doubt that ipilimumab extended survival.

But it did so by three or four months, on average, with some serious adverse events in the treatment group. As I said yesterday, this is the sort of progress that we generally make in oncology, not the oh-my-God-the-cancer-disappeared sort that last year's press release had people thinking about. And again, you can look at this news in two different ways. On the one hand, showing real statistical efficacy against metastatic melanoma is impressive: pretty much everything else we've got does nothing at all. But on the other hand, well. . .three and a half months.

For some people, that's definitely going to be worth it, while for others, they (and their heirs) would be better off not spending the money. That's a very hard decision, one of the hardest, but it is a decision. And either people will make it for themselves, or someone will make it for them. Given the continued emphasis on bringing down the costs of modern medical care - which doesn't look to be going away any time soon - you have to expect that there will be times that governments and/or insurance carriers will say "No, not for that price." Expect? It already happens. But it'll happen more.

This does present a problem for drug discovery. As many commenters noted yesterday, these are the sorts of incremental improvements that can add up in oncology. We're unlikely to hit many miracle-cure home runs, so we have to add a few months here and a few months there, learning as we go, and coming back around with better ideas next time. This takes money - big stacks of it - and we in the industry are expecting people (and their insurance companies, and their governments) to pay up. What if they don't, or not so much?

One thing we could see is companies finding themselves caught out, developing drugs in anticipation of a pricing structure that won't materialize. And it's true that strong pricing pressure will likely slow down progress in the whole field - after all, we don't have any other cheaper ways to develop drugs yet. But that doesn't mean that it couldn't happen. If we want to forestall it, I think we should make clear how incremental and expensive most oncology work is likely to be, and to point out that if there are miracle cures out there, that we're probably not going to find any of them without going through a lot of not-so-miraculous ones first.

June 7, 2010

Let's open up a painful subject here. This is prompted, partly, by the news the other day about Erbulin. The main reason I posted about that compound was because of its chemical complexity and total-synthesis heritage, both of which are unusual. But it's an oncology drug. As such, it looks like an awful lot of other drugs in that space.

And that's not good. Because we should face up to the fact that most of the newer anticancer compounds aren't so good, not in any absolute sense. (Most of the old ones, too, but those are rather cheaper, aren't they?) Too often, what we're looking at is an extension of a few weeks or months of life - life as a terminal cancer patient, mind you, but life nonetheless. The price you put on that will vary according to your circumstances, but in many cases we're asking a lot. Is it worth it?

Increasingly, that's not a question that's going to be answered by the patient alone, but by some combination of the patient and his or her insurance company. In other cases, it will have been answered well before by a country's national health service, when it did a cost/benefit analysis of the drug and decided whether it would even be included in a national formulary. That's the whole point of the UK NICE, and although their execution has not been trouble-free, the idea behind it is not going to go away.

Nor should it. Now, I think people should be able to spend their own money on what they want to spend it on. True, cancer patients are known for spending some of it, out of sheer desperation, on bizarre and worthless stuff. Taking advantage of these people by selling them Wonder Water or Miracle Mixture is a crime, as far as I'm concerned, and should be prosecuted. But I'm not advocating force to keep people from exercising their choice to buy the stuff, if it's out there, although I'd certainly like to talk them out of doing that. I'll reserve the force for the ones selling it, so that the crap is not out there for purchase in the first place.

But when it's other people's money being spent - an insurance company's, or tax money - those others should get a say. And here's where things get messy. Because while there's a difference between Wonder Water and the latest angiogenesis inhibitor or cell-cycle interrupter, it's not a meaningful a difference as anyone would like. True, one is likely to do nothing, and the other is likely to do something. But when "something" is "keeping you from dying in November, in order that you should die in March", well. . .you'd want something more, wouldn't you?

Let me say here that it's not for lack of trying. We in the business keep throwing our best punches in oncology. Here, here's a target that makes perfect sense - this thing should kill a cancer cell. Shouldn't it? I mean, cutting off the blood supply to a solid tumor is a good idea. Messing up mitosis, re-establishing programmed cell death: good ideas. But they just don't work as well as we'd hope that they would. We're not there yet.

And so we get these add-a-few-months-of-life drugs, because in most cases, that's all we're capable of delivering at the moment. But we're asking a lot of money for these things, and increasingly, the people who are really paying for them are asking whether anyone's getting a good deal.

I wrote about this situation a few years ago on this site, and I have to say, not much has changed - other than the pricing pressure, of course. I'll have some more to say about this issue this week, but I wanted to start people thinking - about where we are, and whether there are any ways out.

June 4, 2010

Now here's one that I certainly didn't expect: there's a mouse model of obsessive-compulsive disorder, where the animals have a mutation in the Hoxb8 gene. These animals spend huge amounts of time repetitively grooming themselves (and their cagemates), and eventually remove so much hair that they give themselves lesions. From what I can see, they're doing the usual moves that mice do, but spending a lot more time doing them. And it doesn't seem to be something due to insensitivity to pain; the animals have some sensory alterations, but disrupting Hoxb8 in the spinal cord only doesn't lead to the grooming phenotype.

A new paper from a group at University of Utah reports that the brain signature of Hoxb8 mutation is found only in a population of microglia, one variety of the support cells that surround neurons. Hoxb8 was already known to affect the formation of blood cells, so this cohort of microglia (about 40% of the total in the mouse brain) look to be derived from the same precursors. So this study went the direct route: they did bone-marrow transplants on the mutant mice so that normal Hoxb8 cells would be produced. And over a time scale of weeks,most of the mice stopped their overgrooming. Meanwhile, the group also transplanted mutant bone marrow into normal mice, whereupon some of these mice began obsessively removing hair. (Here's the Nature News article on all this).

This seems to be the first time that anyone's linked microglia with behavior. The focus, naturally enough, has been on the neurons themselves and their connections, but it looks like we're all going to have to broaden our outlook. There are some things that need to be cleared up here, though. For one thing, it's not certain that these mice are truly an analog of human OCD - even the form of it that involves obsessive hair-pulling. Other obsessive mice types are known, and it'll be quite interesting to see what shape their microglia are in. At the same time, it would be worth going the other way, and seeing if the pharmacological agents used for OCD have any affect in the Hoxb8 mice, too.

Another thing that this study demonstrates is that at least one population of microglia are being continually renewed in the brain from the bone marrow. What the different roles are of this group versus the "resident" microglia is yet to be figured out. My mental picture of the brain has always been this protected zone, with very little allowed to cross in or out, but that's clearly incorrect.

But it looks as if we can say that someone has drawn a direct link between the immune/blood cell system and behavior in an animal model. Such things had long been suspected, but they've been very difficult to prove. Whether these mice have OCD or not, they've illustrated something new. This makes me wonder if various immunosuppressive drugs could have psychological and behavioral side effects that we haven't been picking up on - anyone who knows that field care to comment?

I've been hearing a lot about Nativis since my post the other day, much of it from their CEO, who's sent along quite a bit of information. Two themes that reoccur are that the company is planning to publish on their technologies within the next few months, and that they're planning to file for an IND on their taxane-derived work.

Rather than continue to speculate on what the heck is going on with them, then, I'm going to wait until one or both these events happen. Either of them will provide a lot more data to work with, and either one will require convincing other observers that there's something worthwhile going on. Based on what I've seen, I remain skeptical, but there are always things that I haven't seen. We'll take up the topic again.

June 3, 2010

So it looks like the FDA is giving reviewing Eisai's oncology drug Eribulin (E7389) a priority review. The company had hoped to get it reviewed three years ago, but the FDA told them to get back into the clinic and collect more data.
The compound is being reviewed for advanced breast cancer, and the earlier clinical data looked pretty good. (Head and neck tumors, on the other hand, didn't show much of a response). It binds to yet another site on tubulin (a popular site for various oncology agents), but in a rather complicated fashion that differs from the other agents in this category.

The compound is remarkable mainly for its brutal structural complexity, and for the fact that it's being made synthetically. It looks like a natural product, for sure, but it's actually a modified version of the right-hand side of halichondrin B, whose structure is still more horrific. Kishi's group at Harvard synthesized that beast back in 1992, and that work was the foundation of the synthesis of Eribulin. I don't think this is necessarily going to spark a renaissance of Big Natural Product Analog Synthesis inside the pharma labs, but it's quite a story. Here's hoping it has a good ending - we should know in September.

I wrote here about Sequenom, a company which claimed to have developed an in vitro test for Downs Syndrome. The whole story dissolved into a heap of lawsuits, allegations of fraud, questions about whether Sequenom ever had such a test at all, and other craziness.

Now the SEC has charged a former executive of the company with lying to investors. Elizabeth Dragon publicly touted the accuracy of the company's test several times, in front of large groups, before the roof came in. Here's the official complaint (if that doesn't work, try here) and it's most interesting reading:

Dragon knew that all but six of the 51 samples had been tested on an unblinded basis, and also knew that, of the six blinded samples, her scientists incorrectly called one of the three T21 samples. In fact, in an e-mail to her lead scientist, Dragon asked how close the call was when she learned that the third T21 sample had not been called correctly on a blinded basis.

On June 3, 2008, Dragon presented data regarding the Down Syndrome Test at an analyst-and-investor briefing during the ISPD conference, which was simultaneously made available to the public via a webcast. . .The slides in Dragon's presentation indicated that the Test performed with 100% accuracy. . .

. . .Additionally, following her presentation, Dragon was asked a question regarding whether there was ambiguity in calling the samples. In response, she stated that T21 samples were very clear, and that "[t]he overall call is strongly positive . . ., you know it's definitely a Downs and you can read it as a Downs without any problem . . . "

She's also charged with stating that the unblinded tests were, in fact, blinded, and apparently never mentioned that unblinded tests were even being conducted. When blinded tests were run later, their accuracy was below that of the tests already on the market, actually. The SEC charges Dragon with pressuring the scientists involved to drop samples and re-evaluate their calls until the accuracy numbers came up. Her presentation of these runs also showed "100% accuracy", with no false positives and no false negatives. None of it was true.

I'm glad to see this prosecution happening. We live by accurate data, and seeing it sawed off and spray-painted like this makes me furious. If the SEC's allegations are true, I hope it can serve as an example to others who might be tempted to try the same sort of thing.

June 2, 2010

A longtime reader sends me word of a new company out in La Jolla, Nativis Pharmaceuticals, whose technology is most certainly eyebrow-raising. I think that the only way that I can do it justice is to quote directly from their web site; I wouldn't want to get anything wrong:

Nativis has developed and patented a breakthrough technology that captures the unique photon field (signal) of active pharmaceutical ingredients (API), or drugs. . .Every drug molecule in a solution is surrounded by a photon field that contains information unique to the molecule. With Nativis’ technology, the photon field, or “drug signal” can be recorded and then replicated for medical treatment. Nativis has proven in preliminary trials that the drug signal – or photonic signature – mimics the original chemical molecule and can unlock the same biological processes as the original to treat diseases, such as brain tumors. With the technology, the drug signal can be reproduced rapidly and flawlessly, each time containing all relevant biochemical information encoded into the new therapeutic signal to drive a biologic reaction. . .

There now, tell me that your eyebrows didn't get some exercise when you read that. I'm baffled. According to this story from the North County Times, Nativis has investors and advisors who are neither scam artists nor saffron-robed gurus, and unfortunately, the only other appropriate category I can think of is "victim". Am I wrong?

I say that because there have been ripoffs beyond number that claim to use some sort of strangely energized or structured water, which is what seems to be going on here (see below). Honestly, you could easily fill a 500-page book with them, in fine print, and there are more every day. And if the Nativis folks don't want to be taken for another member of that crowd, then they should do more to differentiate themselves from the scam artists (and no, linking to videos of Feynman explaining the basics of quantum electrodynamics is not enough). Here's why I say that - this is the company's explanation of their process:

MIDS (Molecular Interrogation and Data Systems) captures the photon field surrounding the solvation shell of a molecule in solution.

Captured photons are then imprinted into Coherence Domains in dipole (water-based) solution for delivery to patients; following administration, the photon payload chemically activates a non-water molecule for therapeutic effect.

The questions come tumbling out: what, exactly, is a "photon field"? And how do you capture one? Isn't a solvation shell a rather dynamic thing, which depends on (among other things) concentration, ionic strength, and pH? How do you imprint captured photons into something? And "Coherence Domains?" That sounds like optical coherence tomography or the like, but only vaguely. How do you imprint into one? And this creates a "photon payload"? How does that, whatever it is, not dissipate?

And that "chemically activates a non-water molecule", does it? By that, I presume that they mean a drug target. But my understanding of how a drug works on its target is that the drug has to be physically present, because it's interacting, on an atom-by-atom basis, with said target. Drugs engage in a complex dance of attraction and repulsion with their binding sites (with attraction winning out!), and this process is affected by electron density (charge), hydrogen bonding, van der Waals forces, and more besides. The drug molecule physically occupies that binding site, which forces the rest of its target into a different shape. And in many cases, it physically displaces water molecules while doing so, and while it's there, it keeps other molecules from coming in.

I don't see how a "photon payload" can do these things. If it's some real assembly of water molecules, I don't see how it holds together at room temperature. Besides, the water solvation shell of a drug molecule isn't what comes in and binds to a target; it's the molecule itself. Shedding those waters is a key energetic part of the whole process. And if it's not a real, physical assembly of water molecules, then what the heck is it? And here's another objection: either way, it sound as if they're taking this "drug signal" while the original drug is out there in solution. But the shape that most drugs have in solution isn't the one that most drug have when they bind to their targets; adopting that new shape is another key process.

No, I have a weakness for wild ideas, but not this wild. Nativis has a lot to prove: can they take the "drug signal" from a fluoroquinolone antibiotic and kill bacteria with it? Can they use the signal from a receptor agonist and see calcium or cAMP changes in a cell assay? Will the "drug signal" displace a reference compound in a radioligand binding assay? Can you do Michaelis-Menten kinetics with one of an enzyme inhibitor? Will it affect a protein's NMR spectrum? Can you determine its on- and off-rates in an SPR assay? Can you see a thermodynamic signature in a calorimeter?

And most importantly, will it help anyone who's sick? Well. . .Nativis says that they've shown efficacy in a mouse model of glioblastoma with the "drug signal" of taxol. They say that they hope to file an IND later this year, and to publish more details in the literature within the next few months. I cannot wait. If they really have data sufficient for an IND, then I will enjoy, most thoroughly, being proved wrong. And if this stuff works, we can all take the opportunity to learn some physics while glory, prizes, and huge amounts of money rain down on the Nativis folks, to a backdrop of cheering cancer patients.

I am, as this post shows, intensely skeptical. But these are issues that can be answered, completely answered, by experiment. Bring on the data, guys. I'm sticking with the blog category shown until then.

Update: John Butters, CEO of Nativis, has sent along some more information about his company's technology. Much of it seems to be based on work by del Giudice and Preparata on the properties of water. Those names rang a faint bell for me - turns out that their work pops up in all sorts of discussions of odd water effects: cold fusion, homeopathy, theories on the origins of life and of consciousness, and so very much on. I must confess that much of the physics is beyond my competence.

However, this all reminds me very much of homeopathy, and of the Benveniste affair and its aftermath, with many phrases ("digital biology") in common. I have to conclude, for now, that this is what's going on. In which case, I wish everyone involved - particularly the investors - the best of luck, because I have grave doubts that anything useful will come out of it. I will be delighted and amazed if I am proven wrong.

June 1, 2010

Here's an article on a topic that's come up around here before: psychological and cognitive barriers to discovering a new drug. These include confirmation bias, poor risk assessment, an over-reliance on recent experience, etc. The tricky part is that some of these cognitive mistakes might actually be reasonable adaptations to the problems of drug research itself:

The history of science and medicine is full of wrong ideas that prevailed for many years, despite mounting evidence to the contrary: phlogiston, the four humours, spontaneous generation of life and inheritance of acquired traits. These are examples of ‘confirmation bias’, which means that ‘we tend to subconsciously decide what to do before figuring out why we want to do it’ and seek evidence that tends to confirm rather than refute our initial judgment. . . In medicine, such ‘bad science’ can cost many lives; therefore, major institutions and professions have procedures and rules – notably peer review – that seek to protect against the pernicious effects of excessive self-confidence (setting aside, here, the issue of blatant fraud).

In our direct experience, discovery scientists admit that false optimism helps keep them functioning despite the recognized reality that most of their projects fail. This seems an essential trait of scientific heroes of the past yet, paradoxically, might count as a cognitive error in a business setting:

Now there's one that I hadn't considered, although I have thought a lot over the years about the differences between the business side of the industry and the discovery side. I'm not sure that "false optimism" is what keeps me going, though - I try to realize that most projects fail, but I try to make sure that they didn't fail because of something that I did (or didn't do) myself. The authors, though, quote from another study of the same phenomenon, which raises an interesting question:

Given the high cost of mistakes, it might appear obvious that a rational organization should want to base its decisions on unbiased odds, rather than on predictions painted in shades of rose. However. . .optimistic self-delusion is a diagnostic indication of mental health and well-being. . .The benefits of unrealistic optimism in increasing persistence in the face of difficulty have been documented. . . The observation that realism can be pathological and self-defeating raises troubling questions for the management of information and risk in organizations. Surely, no one would want to be governed entirely by wishful fantasies, but is there a point at which truth becomes destructive and doubt self-fulfilling?’

And that brings up a phrase that I use often, that it's easy to sit in the back of a conference room and tell people that their ideas aren't going to work. And you're right well over 90% of the time if you do that, but to what end? I'm going to have to think about this idea of "destructive truth" a bit more, but I wanted to put it out there for comments. I'll return to the whole cognitive bias problem as well, because there's more to it than just this. . .